Only Some Epilepsy Drugs May Raise Suicide Risk

NEW YORK – While all epilepsy drugs carry a warning about an increased risk of suicidal behavior, it may only be certain newer medications that are connected to the hazard, a study published Monday suggests.

In a study of 44,300 UK patients who used epilepsy drugs between 1990 and 2005, researchers found an increased risk of suicide, attempted suicide or "self-harm" only among current users of certain newer medications that have previously been linked to a risk of depression.

The findings, published in the journal Neurology, add to a debate about the Food and Drug Administration's decision, in 2008, to require all epilepsy medications to carry a warning about the risk of suicidal behavior.

The move arose from the findings of an FDA "meta-analysis" of 199 clinical trials testing 11 different epilepsy medications. That analysis, which combined the results of all the trials, found that patients receiving medication had a higher rate of suicidal thoughts and behavior during the study periods than those given a placebo — 0.4 percent, versus 0.2 percent.

The analysis was not, however, able to distinguish whether the risk was associated with any particular drugs. And critics argued that requiring all epilepsy medications to carry a suicide warning was too broad a measure, as the drugs are not all alike.

These latest findings offer some support for that contention. But they do not mean that the drugs implicated in this study are the only ones connected to suicide risk, according to the researchers and others who reviewed the study.

For one, the findings are based on a review of information from a database — a study design that cannot prove cause-and-effect.

Moreover, there were only a small number of documented suicides, suicide attempts or instances of self-harm (self-inflicted injuries without a clear intent of suicide), according to Dr. Frank Andersohn and his colleagues at Charite-University Medical Center in Berlin.

The researchers found 453 cases among all 44,300 patients, based on a UK database of electronic medical records.

They then attempted to look at the risk of suicidal behavior and self-harm according to different categories of epilepsy drug. Topiramate, tiagabine, levetiracetam and vigabatrin were grouped together as newer drugs with a "high" risk of depression — based on the fact that in clinical trials, more than 1 percent of patients using the drugs developed depression.

Another group included four newer medications considered to have a low depression risk: gabapentin (Neurontin), lamotrigine (Lamictal), oxcarbazepine (Trileptal) and pregabalin (Lyrica). The other two groups were barbiturates and older epilepsy drugs like valproate (Depakine, Epilim) and carbamazepine (Carbatrol, Tegretol).

Overall, the researchers found a three-fold higher risk of suicidal behavior or self-harm among current users of the group including topiramate, tiagabine, levetiracetam and vigabatrin, as compared with patients who had not used any epilepsy medication in the past year.

However, the numbers, again, were small.

There were only two cases each among current users of topiramate, levetiracetam and vigabatrin, and none among tiagabine users.

The findings, therefore, need to be "interpreted with caution" and confirmed in future studies, Andersohn and his colleagues write.

The results also differ from those of a study published in April in the Journal of the American Medical Association. In that study, researchers found that new users of gabapentin, lamotrigine, oxcarbazepine and tiagabine had a higher suicide risk than those on topiramate — one of the drugs linked to an increased risk in this latest study.

An editorial published with the study agrees that the research is a "good initial attempt" at looking at a complicated question, but more work is needed.

Epilepsy itself is linked to a higher-than-average risk of depression and suicide, pointed out Dr. Josemir W. Sander of the University College London in the UK, one of the editorial authors. That, he told Reuters Health in an email, can make it hard to "disentangle" the potential effects of epilepsy medications themselves.

"The fact that each study into this issue seems to come up with different answers just confirms my belief that this does not have an easy answer," Sander said.

A limitation of the current study is that it lacked detailed descriptions of patients' epilepsy type and any co-existing psychiatric disorders, according to Sander.

There is "no doubt," he explained, that there are many different subgroups of people with epilepsy, and certain patients are more vulnerable to any increased risk of suicidal behavior linked to medications.

For now, Sander said, it is important for people with epilepsy to have a psychiatric evaluation before starting a new drug — a step the FDA has advised doctors to take.

Indeed, the key message for people with epilepsy is that the most important factor in their risk of suicidal thoughts or behavior is whether they have a history, or a family history, of depression or anxiety, according to Dr. Andres Kanner, a professor of neurological sciences at Rush Medical College in Chicago, and chair of the American Epilepsy Society's task force on the psychiatric aspects of epilepsy.

Certain epilepsy medications may facilitate the development of suicidal thoughts and behavior in vulnerable people, Kanner told Reuters Health, but any risk linked to a drug itself would be small.

"Make sure your doctor knows if you have a history of depression or anxiety," Kanner advised, noting that that includes a personal or family history. The doctor can then consider that in the overall management of a patient's epilepsy.

Going forward, Sander said there remains an "urgent" need for clinical trials looking at individual epilepsy drugs in different subgroups of patients, to get a clearer picture of each medication's full risk "profile."

The study was funded by drugmaker Bayer Schering Pharma, and two co-authors on the work have served as consultants for Novartis and Sanofi-Aventis — makers of two of the medications not linked to suicide risk in this study.

Sander and his co-author on the editorial have ties to several makers of epilepsy drugs — including ones that were and were not linked to suicide risk in this study. The companies include UCB (maker of Keppra), Pfizer (Neurontin) and GlaxoSmithKline (Lamictal).

Kanner has also received research support from various companies that make epilepsy drugs.